Pre-frontal cortex processing disorder speech, gait and limb impairments treatment

ABSTRACT

A methylphenidate, particularly including dextro-threo-methylphenidate, is administered to a subject to treat a speech, gait or limb impairment secondary to a genetically acquired pre-frontal cortex processing disease or disorder, particularly including multiple sclerosis, cerebral palsy, Angelman syndrome, Rett syndrome and Fragile-X syndrome.

PRIOR RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 15/075,375, filed Mar. 21, 2016, now U.S. Pat. No. 9,682,073, issuedJun. 20, 2017, which is a continuation-in-part application of U.S.application Ser. No. 14/971,325, filed Dec. 16, 2015, now U.S. Pat. No.9,408,838, which is a divisional application of U.S. application Ser.No. 14/793,829, filed Jul. 8, 2015, now U.S. Pat. No. 9,307,942, whichis a divisional application of U.S. application Ser. No. 14/453,014,filed Aug. 6, 2014, now U.S. Pat. No. 9,155,502, which is acontinuation-in-part application of U.S. application Ser. No.14/059,541, filed Oct. 22, 2013, now U.S. Pat. No. 8,883,815, which is acontinuation-in-part application of U.S. application Ser. No.14/112,065, filed Dec. 24, 2013, now U.S. Pat. No. 9,089,563, which is aUS 371 National Phase application of PCT/US2012/038312, filed May 17,2012, which claims priority to U.S. Provisional Application No.61/487,847, filed May 19, 2011; and this application also claimspriority to U.S. application Ser. No. 14/736,406, filed Jun. 11, 2015,now U.S. Pat. No. 9,270,712, which is a continuation-in-part applicationof US 371 application Ser. No. 14/112,065, filed Dec. 24, 2013, now U.S.Pat. No. 9,089,563; which applications are incorporated herein in theirentireties by reference thereto.

FIELD OF THE INVENTION

This invention relates to a pharmaceutical intervention and method fortreating a speech, gait or limb impairment, particularly including animpairment secondary to a disease or disorder. This invention alsorelates to a pharmaceutical intervention for a subject with motordeficits in the limbs. More specifically, this invention also relates toa pharmaceutical intervention for treating gait, limb and speechimpairments secondary to a pre-frontal cortex processing a disease ordisorder, particularly wherein there are brain or central nervous systemlesions. More specifically, this invention also relates to apharmaceutical intervention for treating gait or limb abnormalities orimpairments resultant from multiple sclerosis, (MS), cerebral palsy(CP), Angelman syndrome (AS), Rett syndrome (RS) and Fragile-X syndrome(FXS).

BACKGROUND AND DISCUSSION OF THE PRIOR ART

Cerebral palsy (CP) is a non-progressive disease or disorder involvingirreparably damaged or injured areas of the brain, including connectionsbetween the cortex particularly the pre-frontal cortex, and other partsof the brain or central nervous system (CNS) and the muscles in theperipheral nervous system. The National Institute of NeurologicalDisorders and Stroke (NINDS) of the National Institutes of Health (NIH)defines cerebral palsy as any of a number of neurological disorders thatappear in infancy or early childhood and permanently affect bodymovements and muscle coordination but do not worsen over time, and theNIH makes clear that cerebral palsy cannot be cured.

Infantile cerebral palsy (ICP) refers to a disorder affecting movement.Infantile spastic cerebral palsy refers to ICP with spastic motordefects. Generally, infantile spastic cerebral palsy can be separatedinto two groups: (1) the symmetric palsies, including the diplegias,which exhibit symmetric involvement on both sides of all fourextremities but to a greater degree in the legs, and the paraplegias, inwhich the lower extremities are equally involved, and (2) the asymmetricpalsies which include the hemiplegias, monoplegias, triplegias andquadriplegias. The quadriplegias differ from the diplegias in that allfour extremities are more or less irregularly involved often with equalor greater spasticity in the arms.

A most common type of spastic cerebral palsy is spastic diplegia. Mostindividuals with spastic diplegia exhibit scissors gait. Scissors gaitis characterized by adduction and internal rotation at the hip, rigidityand excessive adduction of the leg in swing, flexion at the knee,planton flexion at the ankle and contractions of the spastic muscles.Other cerebral palsy gait impairments include toe down where the toe ispointing down and inward. Such gait impairments result in thetoe-to-heel step as opposed to the correct heel-to-toe step. Toe-to-heelstep in turn causes considerable pain to the individual. Someindividuals may exhibit combinations of such characteristics.

Multiple sclerosis (MS), like cerebral palsy (CP), is a pre-frontalcortex processing disorder, often associated with lesions in the brainor central nervous system (CNS). MS and CP have resultant deficits orimpairments in speech, gait or limb. These impairments include, by wayof example, dysarthric speech, gait or limb abnormalities such as toedown, foot drop, spasms, ataxia and related fatigue. The presentinvention contemplates a pharmaceutical intervention for treating aspeech, gait or limb impairment secondary to pre-frontal cortexprocessing disorder, particularly including MS and CP.

Rett syndrome (RS) is a genetically acquired pre-frontal cortexprocessing disorder having a secondary limb impairment, particularlynon-specific hand wringing. Angelman syndrome (AS), like RS, is also agenetically acquired pre-frontal cortex processing disorder having asecondary limb impairment, particularly non-specific arm flapping, aswell as gait and speech impairments. The present invention contemplatesa pharmaceutical intervention for treating a speech, gait or limbimpairment secondary to a genetically acquired pre-frontal processingdisorder, particularly including RS and AS.

MS and CP, like RS and AS, may be genetically acquired. The MS, CP, RSand AS secondary gait or limb impairments, however, are often latermanifested in the life of the subject. The present inventioncontemplates the pharmaceutical intervention at the onset of theimpairment in a child.

Attempts to treat gait impairments and spasticity include devices suchas a therapeutic chair as disclosed in U.S. Pat. No. 4,145,083, issuedMar. 20, 1979 to Urban; transcranial electrode stimulation as disclosedin U.S. Pat. No. 4,844,075, issued Jul. 4, 1989 to Liss; transcranialmagnetic stimulation as disclosed in US2011/0270345 A1, published Nov.3, 2011 to Johnston et al.; neurosurgery as disclosed in U.S. Pat. No.6,936,049, issued Aug. 30, 2005 to Svadovskiy; botulism toxin asdisclosed in U.S. Pat. No. 7,378,389, issued May 27, 2008 to Graham; andcombinations of botulism toxins with automated movement therapy asdisclosed in US 2008/0279896 A1, published Nov. 13, 2008, to Heinen etal. Heinen et al. discloses pharmaceutical muscle stimulation prior toand in combination with botulism toxin and in further combination withautomated movement interventions. Injectable pharmaceuticals, such asinterferon derivatives, particularly including Plegridy© (peginterferonbeta-1a), are known in the treatment of multiple sclerosis, and suchinjectables cause debilitating pain. Thalidomide and its analogs areknown to treat multiple sclerosis.

Parkinson's disease is a degenerative disorder of the cerebral nervoussystem effecting specific motor systems that result specifically fromthe dearth of dopamine generating in the basal ganglia. Parkinson'sdisease is an idiopathic degenerate disorder that develops usually inindividuals 60 years of age or older. A brain scan of an individual withParkinson's' disease reveals no brain damage, unlike cerebral palsy andmultiple sclerosis. Parkinson's disease is characterized by stiffness orrigidity, slow and decreased movements resulting in gait instability andthe readily recognizable Parkinson's shuffle. Parkinson's gait rigidityis markedly distinguished from cerebral palsy spasticity. Insofar asParkinson's disease results from a loss of dopamine, one treatment isthe administration of dopamine agonists particularly methylphenidate, asdisclosed in Methylphenidate for the Treatment of Gait Impairment inParkinson's Disease; NIH Clinical Trials, pp 1-5; Oct. 27, 2009; anddopamine transporter inhibitors, as disclosed in U.S. Pat. No.8,258,305, issued Sep. 4, 2012 to Hauske.

The art desires a pharmaceutical intervention or treatment for apre-frontal cortex processing disorder resultant speech, gait or limbimpairment that does not require mechanical, electro-mechanical,invasive and toxic interventions.

The art also desires a treatment as aforesaid including a pharmaceuticalintervention and method for treating a speech, gait or limb impairmentsecondary to a genetically acquired pre-frontal cortex processingdisorder.

The art desires a pharmaceutical intervention as aforesaid wherein theimpairment is diminished, and the diminishment in the impairmentpersists and continues over time, even when the pharmaceuticalintervention is no longer efficaciously present.

The art also desires a pharmaceutical intervention as aforesaid as wellas a combination of pharmaceuticals, for the simultaneous treatment of aspeech, gait or limb impairment secondary to MS, CP, AS, RS and FXS.

The art also desires a pharmaceutical intervention for a speech, gait orlimb impairment as aforesaid that is readily administered, efficaciousand safe, with ready and persistent diminishment of the impairment.

The present invention provides a solution to the aforesaid needs.

SUMMARY OF THE INVENTION

The invention, in one principal aspect, is a pharmaceutical interventionfor treating a speech, gait or limb impairment secondary to apre-frontal cortex processing disorder in a subject. The pharmaceuticalintervention is a psychostimulant having mood-elevating orantidepressant activity, particularly an NDRI. In a preferred aspect,the pharmaceutical intervention is a methylphenidate, and mostpreferably dextro-threo-methylphenidate.

The invention is a pharmaceutical intervention as aforesaid forgenetically acquired disorders, particularly including Angelman syndrome(AS) and Rett syndrome (RS).

The invention is a pharmaceutical intervention as aforesaid forgenerally non-degenerative or non-progressive disorders particularlyincluding cerebral palsy (CP) and Angelman syndrome (AS).

The invention is a pharmaceutical intervention as aforesaid whichdisorder was acquired genetically, in utero, at birth or shortly afterbirth, and the impairment later manifested. Genetically acquired and inutero acquired disorders, particularly including cerebral palsy (CP),Angelman syndrome (AS) and Rett syndrome RS), are within thecontemplation of the present invention.

The impairments treated by the pharmaceutical intervention of thepresent invention include, by way of specific examples, dysarthricspeech, limb spasms, toe or foot drop, non-specific hand wringing, andnon-specific arm flapping.

Without wishing to be bound by any theory or mechanism, it is believedthat the administered NDRI, particularly including a methylphenidate,and more particularly dextro-threo-methylphenidate, provides or restoresneural pathways extending from the prefrontal cortex so as to provideimproved processing management and control with consequentialdiminishment in the speech, gait or limb impairment.

Without wishing to be bound by any theory or mechanism, it is alsobelieved that the methylphenidates administered pursuant to the presentinvention may affect or restore neural pathways between upper motorneural lesion areas of the brain and the spine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the % heel-toe-toe as compared to % toe-to-heel step gaitat the initial administration of a pharmacological intervention of thepresent invention and at the time of a subsequent administration of apharmacological intervention pursuant to the present invention forParticipants 1-5A.

FIG. 2 shows the GMFCS level at the initial time prior to and after apharmacological regimen of the present invention for Participants 1-7.FIG. 2 demonstrates that the GMFCS level number after a regimen of thepharmacological intervention of the present invention is at least onelevel number less than before the regimen.

FIG. 3 is a graph of the time spent holding stair railings while goingup and down stairs in an initial visit/examination before and afterpharmaceutical intervention, and in subsequent visits/examinations forParticipant 5A. The solid line is the within the hour measurements at aspecific visit/examination, and the broken line is the timeframe betweenvisits/examinations.

FIG. 4 is a graph of the time spent in a 30 second timeframe inheel-to-toe walking while going up and down stairs at an initialvisit/examination before and after the initial pharmaceuticalintervention, and in subsequent visits/examinations for Participant 5A.The solid line is the within the hour measurements at a specificvisit/examination, and the broken line is the timeframe betweenvisits/examinations.

FIG. 5 is a graph of the percentage time in correct heel-to-toe gaitwhen walking up and down stairs in an initial visit/examination beforeand after the initial pharmaceutical intervention and in subsequentvisits/examinations for Participant 5B.

FIG. 6 is a graph of the percentage time spent keeping the foot turnedout when walking up and downstairs in an initial visit/examinationbefore and after the initial pharmaceutical intervention and insubsequent visits/examinations for Participant 5B.

FIG. 7 is a graph of the time spent in seconds over a 60 secondtimeframe with the ankle turned inwards and crossing over the ankle whenwalking in an initial visit/examination and in subsequentvisits/examinations for Participant 6.

FIG. 8 is a graph of the distance covered in steps walking on a flatsurface attempting to traverse a course at an initial visit/examination,and traversing the course in subsequent visits/examinations forParticipant 6.

FIG. 9 is the time spent in nonspecific hand wringing while walkingmeasured at visits/examinations during the pharmacological interventionregimen for Participant 6.

FIG. 10 is a graph of the time to place the feet on the ground and pickthe body up from a seated position to standing with a walker invisits/examinations for Participant 7.

FIG. 11 is a graph of time spent to walk 10 feet during the course ofthe pharmacological interventions for Participant 7.

DESCRIPTION OF THE INVENTION

The term “subject” as used hereinbefore and hereinafter means a human orother mammal, and includes a patient, or a participant in a study orclinical trial.

The term “therapeutically effective dose” or “therapeutically effectivedosage” as used hereinbefore and hereinafter means an amount of theadministered substance that is sufficient to provide a diminishment ofthe impairment.

The term “psychostimulant” as used hereinbefore and hereinafter isbroadly defined to include an NDRI having antidepressant ormood-elevating properties, and as further discussed hereinafter.

The terms “MPH” and “MPD” as used hereinbefore and hereinafter refer toracemic methylphenidate.

The term “genetically acquired” or “acquired genetically”, as usedhereinbefore and hereinafter includes genetically inherited defects andmutations, and chromosomal defects, as well as genetically transmittedor pre-dispositioned disorders.

The term or acronym “GMFCS” means Gross Motor Function ClassificationSystem. The gross motor skills (e.g. sitting and walking) of childrenand young people with cerebral palsy can be categorized into 5 differentlevels using a tool called the Gross Motor Function ClassificationSystem (GMFCS). The GMFCS levels are: Level 1—walks without limitations;Level II—walks with limitations. Limitations include walking longdistances and balancing, but not as able as Level I to run or jump; mayrequire use of mobility devices when first learning to walk, usuallyprior to age 4; and may rely on wheeled mobility equipment when outsideof home for traveling long distances; Level III—walk with adaptiveequipment assistance. Requires hand-held mobility assistance to walkindoors, while utilizing wheeled mobility outdoors in the community andat school; can sit on own or with limited external support; and has someindependence in standing transfers; Level IV—self-mobility with use ofpowered mobility assistance. Usually supported when sitting;self-mobility is limited; and likely to be transported in manualwheelchair or powered mobility; and Level V—severe head and trunkcontrol limitations. Requires extensive use of assisted technology andphysical assistance; and transported in a manual wheelchair, unlessself-mobility can be achieved by learning to operate a poweredwheelchair.

The terms “visit”, “examination” or “visit/examination” refer to anexamination of the Participant by a pediatric neurologist.

The present invention includes the administration of a therapeuticallyeffective dose of one or more of a broad range of NDRIs or dopamineagonists including a methylphenidate, particularly includingdextro-threo-methylphenidate, (Focalin®), and the non linear lower alkylphenidates, particularly including isopropylphenidate.

The present invention treats subjects, particularly children, diagnosedwith cerebral palsy having secondary disorders including both a gaitimpairment and a speech impairment. The treatment of speech impairmentsecondary to cerebral palsy is disclosed in co-pending application Ser.No. 14/453,014, filed Aug. 6, 2014, and in parent application Ser. No.14/059,541, filed Oct. 22, 2013, now U.S. Pat. No. 8,883,815, whichreferences are incorporated herein in their entireties by referencethereto.

The present invention contemplates a combination of two medicaments, afirst medicament that efficaciously treats a certain disease or disorderbut has an adverse side effect, namely a gait or limb abnormality orimpairment and/or speech impairment, and a second medicament namely apsychostimulant having mood elevating or anti-depressant properties,particularly including a methylphenidate, that diminishes the gait, limbor speech impairment.

The art discloses that thalidomide can be used in the treatment of ALS,as disclosed in US Pub. 2005/0182097, published Aug. 18, 2005 to Zeldiset al. The present pharmaceutical intervention may likewise be used totreat speech, limb or gait impairments resultant from or in combinationwith the thalidomide or an analog treatment of the genetically acquiredALS and other genetically acquired disorders.

It is also within the contemplation of the present invention to combineor co-administer thalidomide or a thalidomide analog, or Abraxane® knownto have gait abnormalities side effects with the psychostimulant of thepresent invention, particularly methylphenidate, and more particularlydextro-threo-methylphenidate, to efficaciously treat the disorder whilediminishing or precluding the gait, limb and speech impairments incidentto a thalidomide regimen, Abraxane® regimen or to the disease ordisorder. Limb impairments incident to seizures, particularly epilepticseizures, are also within the contemplation of the present invention.

It has been surprisingly found that the pharmaceutical intervention andmethod of the present invention diminishes the aforesaid impairments,which diminishment in impairments and pain persists even when thepharmaceutical intervention is no longer efficaciously present.

EXAMPLES

Participant 1

Participant 1 is a male and was 8 years old at the time of the firstpharmacological intervention pursuant to the present invention.Participant 1 had delayed speech and language. Participant 1 wasdiagnosed as having spastic dipligea, bilateral contractures at thehips. Participant 1 wore leg braces prior to the pharmacologicalintervention, and the braces were removed in the initial visit. Prior tothe pharmacological intervention of the present invention, Participant 1was treated with Botox injections, oral baclofen and orthotics. Theparents of Participant 1 stopped all such treatments because they didnot observe any improvement in gait.

The initial pharmacological intervention was 2 cc (10 mg) of QuillivantXR®, and one month later was replaced with 5 mg of racemicmethylphenidate (MPD)/day. FIGS. 1-2 for Participant 1 shows theimprovement in gait after about 45 minutes at the initial visit, andafter daily treatments of 5 mg methylphenidate/day.

Participant 2

Participant 2 is a female and was 15 years old at the time of theinitial pharmacological intervention pursuant to the present invention.Participant 2 did not start to walk until 18 months of age, and hadsignificantly delayed speech and language development. She was notspeaking in sentences until she was 5 years of age.

Participant 2 was diagnosed with spastic dipligea and painful gait.Participant 2's weight increased because of the avoidance of walking topreclude the concomitant pain.

After about one year of daily methylphenidate administrations,Participant 2 could walk on a flat surface and up and down stairs withflexibility, even when the methylphenidate is no longer efficaciouslypresent in the body.

Participant 2 reports she is pain free, has entered the school talentshow and exhibits a 15 minute dance routine performed at school.

Participant 3

Participant 3 is a female and was about 15 years of age at the firstpharmacological intervention pursuant to the present invention.

Participant 3 had an initial diagnosis of cerebral palsy, epilepticencephalopathy, global development delay, left hemiplegia and spasticdipligea, left greater than right. At the initial visit, Participant 3was physically examined and found to have a limited amount of receptiveand expressive language, with the left side of the body much smallerthan the right side, left hemiplegia, contractions of the left elbow,and unable to open left hand, with the fingers and thumb kept in fistedposition. Participant 3 loses balance and falls if not assisted whenrising from a chair. When walking on a flat surface, she keeps her leftelbow at 90 degrees, left hand remains in a fisted position, toe-to-heelgait, bilateral left greater than right. And to avoid tripping over herleft foot, she keeps her left foot in extension securing her left leg asfar away from her trunk in order for her left foot to have enoughclearance to avoid first hitting the ground with the extremities.

A 400 mg/day Gabapentin® regimen was prescribed. After 2 months, therewas a 5 mg MPD initial administration. This was followed by 5 mg MPD/dayfor a period of 11 months. FIGS. 1-2 show Participant 3 gait improvementat the initial intervention, and after the 11 months of the foregoingregimen.

Participant 3 reports playing sports, even when the MPD is no longerefficaciously present.

Participant 4

Participant 4 is a female, and was about 19 years of age at the time offirst pharmacological intervention of the present invention. Participant4 was born prematurely at 24 weeks. Participant 4 had a twin. The twindied on day one. Participant 4 suffered hypoxia at birth. Participant 4first began to walk and talk well over 2 years of age. Participant 4 wasdiagnosed with cerebral palsy and global developmental delay,Hashimoto's thyroiditis, epilepsy, scoliosis and spastic dipligea. AnMRI of the brain revealed periventricular leukomalacia. The initialvisit revealed that Participant 4 walks with a crouched gait, flexed atthe hips and knees, lateral fixed contractions, and obligated toe toheel gait with pain when walking and calf muscular pain when notwalking. Medication administered long prior to and during thepharmacological intervention of the present invention included theanti-seizure medicament oxcarbazepine (Trilepal®). Oxcarbazepine(Trilepal®) is reported to cause gait abnormalities as a side effect.

The improvements in gait and step after the two weeks of daily MPDadministration are shown in Table I.

TABLE I Heel-to-Toe/ Stairs Holding Stairs Holding Toe-to-Heel toRailings Up Railings Down (Sec./Sec.) (Sec./Sec.) (Sec./Sec.) Initial9.38/15 Initial 7.4/59 Initial 12.81/59 After 2  15/15 After 2  0/60After 2    0/60 Weeks Weeks Weeks

Participant 4 Example demonstrates improvements in gait including stepwith co-administration of an anti-seizure medicament having a gaitimpairment side effect.

It is within the contemplation of the present invention to combine thepresent pharmacological intervention with a medicament for treating adisease or disorder but with gait abnormality or impairment sideeffects, whereby the disease or disorder is treated and the impairmentside effects are precluded or diminished, particularly as demonstratedin the Participant 4 Example.

Participant 5A

Participant 5A is a female 13 years of age at the time of the firstexamination pursuant to the present invention. Participant 5A has anidentical twin; hereinafter referred to as Participant 5B. Participants5A and 5B were born to a drug addicted alcoholic woman and werediagnosed with speech and gait impairments secondary to cerebral palsy.Participant 5A had a speech-language disorder and spastic diplegia.Participant 5A had to direct both legs in extension to avoid trippingover her own feet because she was unable to flex and extend at the anklejoint to move her feet, resulting from the spastic dipligea.

At the first visit/treatment, 5 mg of methylphenidate was administeredto Patent 5A. Prior to the administration, Participant 5A had noheel-to-toe functionality. After administration, Participant 5A hadgenerally 43% heel-to-toe walking time in both feet in walking and upand down stairs. See FIG. 1. Participant 5A reported no pain afterwalking.

Referring specifically to FIGS. 3 and 5, there is shown the dramaticimprovement in heel-to-toe steps in traversing stairs, for Participant5A, particularly with a Focalin® regimen in lieu of a racemicmethylphenidate regimen.

Participant 5B

Participant 5B is the identical twin of Participant 5A. Participant 5Bwas diagnosed with severe speech impairment secondary to cerebral palsy.Participant 5B, unlike her twin sister, Participant 5A, did not havequite as severe gait impairment. Participant 5B, however, could not keepher foot straight and had to hold onto railings ascending or descendingstairs.

In the first examination, because the speech impairment was so severe,Participant 5B was diagnosed as mentally retarded. There was novolitional speech. Participant 5B could not read or comprehend at asecond grade level.

In the second examination, a regimen of 5 mg MPD/day was prescribed, tobe taken before school.

At the beginning of the third examination, about one month after thesecond examination, 5 mg MPD was administered. After 40 minutes,Participant 5B had spontaneous speech of 4-6 words, as opposed to the2-3 word capability in the first examination. Participant 5Bcomprehended at a second grade level. A revised regimen of 10 mg MPD/daybefore school was prescribed.

A fourth examination occurred approximately one month after the thirdexamination. Participant 5B was administered 10 mg Focalin®. After 40minutes, Participant 5B was able to keep her foot straight in walkingand did not feel like she was going to fall.

Participant 5B had a regimen of 10 mg/day Focalin® for the next 14 days.A fifth examination was undertaken after the 14 days of Focalin®. At thebeginning of the fifth examination, a 10 mg dose of Focalin® wasadministered. After 45 minutes, Participant 5B had a completeunderstanding of a book that demonstrated comprehension at a 7^(th)grade level. This level of comprehension persisted even when theFocalin® was no longer efficaciously present.

Referring specifically to FIG. 6, there is shown the improvement in thepercentage time keeping the foot turned outwardly as opposed to inwardlytoe down, in traversing stairs for Participant 5B. The improvement ismost dramatic with a Focalin® regimen in lieu of a racemicmethylphenidate regimen.

The Participants 5A and 5B Examples demonstrate diminishments in bothspeech and gait impairments secondary to cerebral palsy. Theimprovements in gait speech and comprehension were particularlysignificant with a regimen of daily administrations of Focalin®.

Participant 6

Participant 6 is a female. At 2-3 years of age she was diagnosed withcerebral palsy.

Participant 6 had an initial visit or examination when she was 8 yearsold. A gait impairment, constant hand wringing and an apraxia of speechwere observed. The gait impairment was a scissors gait with the ankleturning inwards and crossing over when walking.

A 5 mg MPD dose was administered to Participant 6. After 40 minutes,there was a noticeable improvement in gait. A regimen of 5 mg MPD/daywas prescribed and continued for one year, at which time the dose wasincreased to 5 mg MPD/twice daily; once after breakfast and once afterlunch. Observations for Participant 6 in subsequent visits/examinationsare reported in the FIGS. 6-9, and were taken when Participant 6 was offMPD for 24 hours.

In the course of the afore-described treatment, a genetic work-up wasprescribed. It was determined that Participant 6 had a polymorphismheterozygote genetic defect, namely a mutant MECP2 gene. Consequentiallyshe was diagnosed as having Rett syndrome. Participant 6 was observed ashaving a motor apraxia. She exhibited constant nonspecific hand-wringingconsistent with Rett syndrome.

Rett syndrome (RS) is a neurodevelopment disorder that affects girlsalmost exclusively. In nearly all cases of Rett syndrome, there is amutation in the methyl CpG binding protein 2, or MECP2 gene. Thesymptoms are generally overlooked in the early stages. As the syndromeprogresses, the child has jerkiness in limbs and gait impairments, andthe child loses purposeful use their hands, characterized as constanthand washing or non-specific hand-wringing. In later stages, apraxia andparticularly an apraxia of speech occur. There is no known cure for Rettsyndrome, and the life expectancy at best is about 40 years, as reportedin the NIH National Institute of Neurological Disorders and Stroke(NINDS) “Rett Syndrome Fact Sheet,” NINDS Pub. November 2002, updatedFeb. 23, 2015.

Referring specifically to FIGS. 7-9, there is shown the improvement ingait for Participant 6 in an MPD regimen over the course of a two yearperiod. Participant 6 showed continued improvement in motor planning andexecution, particularly the elimination of ankle inwards and toe downimpairments. Prior to Oct. 17, 2013, Participant 6 was able to traverseonly 25 feet in 60 seconds, and by May 22, 2015, Participant 6 was ableto traverse 66 feet in 60 seconds. These improvements resulted from thediminishment in motor apraxia and elimination of the nonspecifichand-wringing while walking.

As demonstrated in FIG. 2 and FIGS. 7-9, the MPD course of treatmentresulted in a GMFCS improvement from level number 3 to level number 1,essentially a complete diminishment of scissors gait and an essentiallycomplete diminishment of the hand-wringing. Speech language equivalenceimproved dramatically over the course of treatment evidencing ordiminishment of the apraxia of speech.

The Participant 6 Example demonstrates the pharmaceutical treatment oflimb impairments, particularly including nonspecific hand wringing andan apraxia of speech secondary to Rett. syndrome.

Participant 7

Participant 7 is a female born in 2004. The first examination was whenParticipant 7A was about 3 years and 4 months of age. Participant 7 hadno speech. Participant 7 was diagnosed with bilateral ankle clonus,bilateral Babinski and spastic dipligea. Participant 7 was in awheelchair. An MRI revealed brain damage consistent with cerebral palsy.

The second examination was when Participant 7 was 4½ years of age.Participant 7 remains in a wheelchair. Participant 7 was able to moveher legs but not sequentially while sitting in the wheelchair.Participant 7 has leg braces.

The third examination determined that Participant 7 is not healing wellbecause of the continued wearing of the leg braces.

The fourth examination was about three years after the thirdexamination. Participant 7 is about 8 years of age. One month prior tothe fourth examination, Participant 7 was prescribed 5 mg MPD/day. Atthe fourth examination, 5 mg MPD was administered. Participant 7, withassists, was able to get out of the wheelchair and had a somewhat moreappropriate posture. A regimen of 5 mg MPD in the morning and in theevening was prescribed.

The fifth examination was one month after the fourth examination. It wasreported by the mother and caretakers that Participant 7 was speakingmore than she had in the prior month. Participant 7 shows furtherimprovement in moving her legs in the wheelchair. The braces remain.

The sixth examination is one month after the fifth examination.Participant 7 is speaking more. The braces remain.

There is then a 2½ year hiatus during which there are no furtherexaminations or pharmaceutical administrations pursuant to the presentintervention. The examinations resumed after the 2½ year hiatus.

At the eleventh examination, the braces remain and appear to have beenin place essentially during the entire 2% year hiatus. There were bracemarks on her legs as a result of the extended usage. The Participant 7legs became weaker. The Participant 7 sedentary life style in turncaused worsened or exacerbated pain in attempts to get out of thewheelchair and stand, and then walk with a walker.

In the course of subsequent visits (examinations 12^(th) and 13^(th)),in a period of about one month, Participant 7 was on a daily dosageregimen of 5 mg MPD, and then 5 mg Focalin®. Two weeks after theeleventh examination, it was agreed to remove the braces permanently.Two weeks thereafter, when Participant 7 had no longer been on MPD for24 hours, Participant 7A exhibited the ability to stand up from thewheelchair with greater ease, to more readily walk and turn with awalker. She was more able to lift her feet and was less prone totripping.

FIG. 10 shows the time spent (in seconds) unassisted in standing up fromthe wheelchair to a walker for Participant 7 during the 11^(th) (Apr.17, 2015), 12^(th) (May 1, 2015), and 13^(th) (May 22, 2015)examinations.

Referring specifically to FIGS. 10 and 11, Participant 7 was on aregimen of 5 mg/day Focalin® in a period from the May 1, 2015visit/examination to the May 22, 2015 visit/examination. FIGS. 10 and 11demonstrate the dramatic improvement with a Focalin® regimen over abouta three week period.

The Participant 7 Example demonstrates that a sustained regimen of MPDand particularly Focalin, with the removal of leg braces, effectedsignificant diminished impairment, particularly the ready ability tolift out of a wheelchair and use in a walker without tripping.

Participant 7 had accordingly improved from a level 5 GFMCS to a level 3GFMCS as shown in FIG. 2. This is a surprising and unexpected resultinasmuch as generally a child at GFMCS level 5 will not improve butremain at a GFMCS level 5.

Participant 8

Participant 8 is a 39 year old male had been diagnosed with primaryprogressive multiple sclerosis (MS).

Participant 8 had a long history of difficulty in walking, particularlyin traversing stairs, and more particularly in downwardly traversingstairs.

Participant 8 had, over the course of many years, been prescribeddiverse medicaments including imuran, baclofen, as well as topicalcortisone for pain after injections.

At the time of the initial examination, pursuant to the presentintervention, Participant 8 was taking injections of Plegridy®(peginterferon beta-1a) every two weeks.

The initial examination, pursuant to the present intervention, revealedthat the subject had a 20/200 right eye and was legally blind in theright eye. The eyes, however, moved equally and symmetrically in alldirections. The subject's reflexes were 2+ everywhere with the exceptionof the left achilles reflex, which was absent. There was no ankleclonus. There was difficulty in balancing. There was cerebellar gait,minimally and wide based. Participant 8 had difficulty making turns,walking stairs, especially walking down stairs. The subject complainedof leg spasms. The subject reported infrequent episodes of not beingable to hold onto a pencil or utensil.

An MRI revealed right parietal and parafalcine lesions with involvementof the right frontal lobe and optic nerves.

Participant 8 was taken off all prior medications and prescribed a dailydose regimen of 5 mg. generic Focalin. After one month of the genericFocalin regimen, the subject was examined.

Participant 8 reported that he no longer experienced pain in his ankles.He reported walking up and down stairs with increasing speed. His stridelength increased. And he is making turns on flat surfaces and stairwayswithout hesitation.

Prior to the present intervention, Participant 8 took 15.4 seconds to goup and down a specific flight of stairs. After the present intervention,Participant 8 transversed the stairs up and down in 12.0 seconds. Priorto the present intervention, Participant 8 required 7.0 seconds to godown the flight of stairs. After the present intervention, Participant 8required only 4.0 seconds to go down the flight of stairs.

Particularly suitable psychostimulants pursuant to the present inventioninclude the norephinephrine-dopamine reuptake inhibitors (NDRIs)including, by way of example, methylphenidate, modafinil, armodafiml anddextro-methylphenidate, as discussed in co-pending applicationPCT/US2012/038312, filed May 17, 2012, and U.S. Ser. No. 14/112,065,filed Oct. 16, 2013, incorporated herein by reference thereto. Extendedrelease, controlled release and immediate release forms methylphenidateare contemplated as useful psychostimulants. Immediate releasemethylphenidate is a preferred psychostimulant.

Preferred psychostimulants further include the lower alkyl phenidates,such as disclosed in Schweri et al., [³ H] Threo-(±)-MethylphenidateBinding to 3,4-Dihydroxyphenylethylamine Uptake Sites in CorpusStriatum: Correlation with the Stimulant Properties of Ritalinic AcidEsters, J. of Neurochemistry, vol. 45, no. 4, pp. 1062-70, (1985), andPortoghese et al, Relative Hydrolytic Rates of Certain Alkyl (b)dl-α-(2-Piperidl)-phenylacetrates, J. Pharmaceutical Science, vol. 50,no. 6, pp. 494-51, and U.S. Pat. No. 6,528,530, issued Mar. 4, 2003 toZeitlin, et al. Preferred psychostimulants also include the nonlinearlower alkyl phenidates, namely isopropyl, isobutyl, d-isoproyl,d-isobutyl, d-threo-isopropyl, d-threo, isopropyl, sec-butyl andt-butyl.

Alkyl phenidates, racemic mixtures and isolated individual isomers areknown in the art, as disclosed in U.S. Pat. No. 2,507,631, issued May16, 1950 to Hartmann et al, U.S. Pat. No. 2,157,880, issued Oct. 25,1960 to Rometsch, and U.S. Pat. No. 5,908,850 issued Jun. 1, 1999 toZeitlin et al; which references are incorporated herein in theirentireties by reference thereto. Alkyl phenidates are commerciallyavailable, including by way of specific examples,dextro-threo-methylphenidate (Focalin®) and isopropylphenidate.

Without wishing to be bound by any theory or mechanism, it is believedthat the nonlinear lower alkyl phenidates provide hindrance tounwarranted esterfication which in turn causes adverse side effects,particularly adverse in children.

In the art related to the treatment of hyperactivity in children,particularly including ADD and ADHD, it is established practice toadminister methylphenidate. Psychosocial behavioral disorders such aslack of attentiveness and verbal regression are improved with theadministration of methylphenidate, as disclosed in U.S. Pat. No.6,121,261, issued Sep. 19, 2006 to Glatt et al; and Creager et al.,Journal of Speech and Hearing Research, 623-628 (1967). Methylphenidateis administered daily to children suffering psychobehavioral andneuropsychological disorders. The behavioral improvement is short lived,and lasts, at most, several hours after administration of themethylphenidate. Unless such daily dosages are maintained, the subjectreverts to his or her attention deficits and hyperactivity.

One further most preferred methylphenidate is an extended release powderin aqueous suspension as disclosed in US 2013/0004571 A1, published Jan.3, 2013 to Metha et al., which is incorporated herein in its entirety byreference thereto. The aqueous suspension is particularly administrableto children with infantile cerebral palsy.

Gaboxadol®, also known as4,5,6,7-tetrahydroisoxazolor(5,4-c)pyridine-3-ol (THIP), and its analogsare contemplated to treat Angelman syndrome and Fragile-X syndrome(FXS). The present invention contemplates a psychostimulant,particularly including a methylphenidate, in combination with THIP or ananalog of THIP to treat speech, gait or limb impairments secondary to ASor to a THIP regimen resultant impairment.

Thalidomide and its analogs are contemplated to treat multiple sclerosis(MS). The present invention contemplates a psychostimulant, particularlya methylphenidate, in combination with thalidomide or an analog to treatspeech, gait and limb impairments secondary to MS or thalidomide regimenresultant.

The foregoing Examples demonstrate that pre-frontal cortex processingdisorders diseases or disorders having secondary speech, gait and limbimpairments.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the subject being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. In combination: (a) a therapeutically effectivedose of a first drug for treating a disease or disorder, said disease ordisorder effects a speech, gait or limb impairment, or wherein the firstdrug effects a speech, gait or limb impairment, in a subject in need oftreatment for the impairment; and said disease or disorder comprises adisease or disorder effecting seizures, wherein the disease or disorderis genetically or in utero acquired, and said first drug comprisesoxcarbazepine; and (b) a therapeutically effective dose of apsychostimulant having mood elevating or anti-depressant activity, saidpsychostimulant comprises a norepinephrine dopamine reuptake inhibitor(NDRI); wherein (b) comprises a nonlinear lower alkyl phenidate, whereinthe non linear lower alkyl phenidate comprises isopropylphenidate;whereby the combination of (a) and (b) treats the disease or disorderand the impairment.
 2. The combination of claim 1, wherein the diseaseor disorder comprises a genetically or in utero acquired disease ordisorder.
 3. The combination of claim 1, wherein the subject is a child.4. The combination of claim 1, wherein the disease or disorder and theimpairment are simultaneously treated, whereby the impairment isdiminished with diminishment of the seizures.
 5. The combination ofclaim 1, wherein the disease or disorder comprises cerebral palsy (CP).6. The combination of claim 1, wherein the disease or disorder comprisesmultiple sclerosis (MS).
 7. A pharmaceutical intervention treating agait or limb impairment secondary to a pre-frontal cortex processingdisorder comprising multiple sclerosis (MS) in a subject in need of suchintervention, said pharmaceutical intervention comprises anorepinephrine dopamine reuptake inhibitor (NDRI); and a pharmaceuticalintervention treating the MS; whereby the gait or limb impairment isdiminished.
 8. The pharmaceutical intervention of claim 7, whereby thediminishment in the impairment persists when the NDRI is no longerefficaciously present.
 9. The pharmaceutical intervention of claim 7,wherein the NDRI comprises a methylphenidate (MPH).
 10. Thepharmaceutical intervention of claim 9, wherein the MPH comprises dextromethylphenidate.
 11. The pharmaceutical intervention of claim 7, whereinthe NDRI comprises isopropylphenidate.
 12. The pharmaceuticalintervention of claim 7, wherein the impairment comprises ataxia. 13.The pharmaceutical intervention of claim 7, wherein the NDRI comprisesmethylphenidate (MPH) and the diminishment in the gait or limbimpairment persists when the MPH is no longer efficaciously present.